Mycobacterium tuberculosis infections cause 9 million new tuberculosis cases and 1.5 million deaths annually1. To identify variants conferring risk of tuberculosis, we tested 28.3 million variants identified through whole-genome sequencing of 2,636 Icelanders for association with tuberculosis (8,162 cases and 277,643 controls), pulmonary tuberculosis (PTB) and M. tuberculosis infection. We found association of three variants in the region harboring genes encoding the class II human leukocyte antigens (HLAs): rs557011[T] (minor allele frequency (MAF) = 40.2%), associated with M. tuberculosis infection (odds ratio (OR) = 1.14, P = 3.1 × 10−13) and PTB (OR = 1.25, P = 5.8 × 10−12), and rs9271378[G] (MAF = 32.5%), associated with PTB (OR = 0.78, P = 2.5 × 10−12)—both located between HLA-DQA1 and HLA-DRB1—and a missense variant encoding p.Ala210Thr in HLA-DQA1 (MAF = 19.1%, rs9272785), associated with M. tuberculosis infection (P = 9.3 × 10−9, OR = 1.14). We replicated association of these variants with PTB in samples of European ancestry from Russia and Croatia (P < 5.9 × 10−4). These findings show that the HLA class II region contributes to genetic risk of tuberculosis, possibly through reduced presentation of protective M. tuberculosis antigens to T cells.
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The authors thank the study participants and the staff at the Patient Recruitment Center and the deCODE genetics core facilities. We thank S. Balen (University of Rijeka) and M. Balija (Croatian Institute for Transfusion Medicine) for assistance in the collection of blood samples, S. Grle-Popovic for assistance in collection of blood samples of tuberculosis patients treated at the University Hospital Center, Zagreb, and J. Pavelic (Ruđer Bošković Institute) for providing resources and advice. This work was supported by the US National Institute of Allergy and Infectious Diseases grant HHSN266200400064C (deCODE Genetics, A. Kong, K.G.K., M.G., M.K.), UK Wellcome Trust grants 088838/Z/09/Z and 095198/Z/10/Z (S.N.), EU Framework Programme 7 Collaborative grant 201483 (University of Cambridge and S.N.), European Research Council Starting grant 260477 and Royal Society grants UF0763346 and RG090638 (S.N.). S.N. is also supported by a Wellcome Trust Senior Research fellowship and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre.
G.S., D.F.G., B.V.H., L.J.G., A.G., S.A.G., H.T.H., Adalbjorg Jonasdottir, Aslaug Jonasdottir, A. Karason, H.K., O.T.M., P.S., A. Kong, G.M., U.T., I.J. and K.S. are employed by deCODE Genetics/Amgen, Inc.
Integrated supplementary information
Q-Q plots using uncorrected (red) and corrected (blue, using the method of genomic control) χ2 statistics from the tuberculosis GWAS of pulmonary tuberculosis, all tuberculosis and M. tuberculosis. All P-values below 0.05 are plotted.
The figure shows first two principal components of the Icelandic cases and controls used in the association. Pulmonary tuberculosis, all tuberculosis and M. tuberculosis infected cases are plotted in blue, and population controls in black.
Supplementary Figures 1–2, Supplementary Tables 1–6 and 8–12, and Supplementary Note (PDF 1644 kb)
Association signals of imputed classical HLA alleles with PTB in Iceland. HLA alleles at four digit levels were established using imputation of sequence data from a set of 2,614 whole-genome sequenced individuals (XLSX 38 kb)
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Sveinbjornsson, G., Gudbjartsson, D., Halldorsson, B. et al. HLA class II sequence variants influence tuberculosis risk in populations of European ancestry. Nat Genet 48, 318–322 (2016). https://doi.org/10.1038/ng.3498
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